1-{8 3-(4-metrachlorophenyl-1-piperazinyl)-propyl{9 -3,4-diethyl-{66 {11 -1,2,4-triazolin-5-one

ABSTRACT

The novel compound 1-(3-(4-metachlorophenyl-1-piperazinyl)propyl)-3,4-diethyl- Delta 2-1,2,4-triazolin-5-one having hypotensive and analgesic activity is disclosed.

United States Patent [191 Palazzo [451 Dec. 31, 1974 [73] Assignee: Aziende Chimiche Ruinite Angeline Franceso A.C.R.A.F. S.p.A., Rome, Italy [22] Filed: Oct. 15, 1973 [2]] Appl. No.2 406,432

[30] Foreign Application Priority Data 0a. I6, 19 72 Italy 53380/72 [52] US. Cl 260/268 PH, 260/308 C, 424/250 [5i] Int. Cl C07dl 51/70 [58] Field of Search 260/268 PH, 308 C Primary Examiner-Donald G. Daus Assistant Examiner.lose Tovar A ttorney, A gent, br Fi rin ladas, Parry, Von Gehr, Goldsmith & Deschamps [5 7 ABSTRACT The novel compound I-[3-(4-metachlor0phenyl-lpiperazinyl)-propyI]-3 ,4-diethyI-A I ,2,4-triazolin- S-one having hypotensive and analgesic activity is disclosed.

1 Claim, No Drawings H c l I I 1 1- 3- 4-METRAc'iiLoRoPHENYL-1- PIPERAZINYL)-PROPYL]-3,4-DIETHYL-A-l,2,4- TRIAZOLIN-S-ONE BACKGROUND or THE- INVENTION This invention relates to a new chemical compound .which has lt ypotensive and analgesic activity without possessing high toxicity. 7

., SUMMARY OFTHE INVENTION The novel compound of this invention is l-[3-(4- metachlorophenyl-l-piperazinyl)propyl]-3,4-diethyl- A -l,2,4,-triazolin-5-one,,designated as having the following formula (I):

and the pharmaceutically acceptable salts thibr'nd the preparation of this compound and its salts.

to the scheme:

2 cation o f the animal behavior, which is typical of tranquilliz ers, and is characterized by sedation, a reduced activity towards the experimentor and a lower motor activity. Moreover, a hypotensive and analgesic activity are observed with (I); the first is evident both in the normal and in the hypertensive rat, the second is evident in the phenylquinone test and in the tail writhing test. Since (I) is scarcely toxic both in acute and chronic tests, it could be interesting as an anti-anxiety and, in general, as a tranquillizer in human therapy.

IIIETAILED DESCRIPTION OF THE INVENTION A process of preparation of (I) consists in the reaction between the known 3,4-diethyl-A -l,2,4-triazolin- 5-one and a suitablesubstituted piperazine, according H5 2\ t I I I L X(CH2)3VN iv Can be used as a salt with mineral acids such as, for

instance, hydrogen chloride, sulfuric acid, phosphoric.

acid, etc., or with aliphatic monoor poly-carboxylic acids, such as formic acid, acetic, lactic, succinic, ma-

45 Ionic, glutaric, adipic, tartaric, citric, maleic, fumaric acid, etc., or with aromatic acids, such as benzoic, salycilic, pamoic acid, etc., or with mandelic, diphenylacetic, benzylic acid, etc., or with sulfonic acids, such as methanesulfonic,' benzenesulfonic, toluenesulfonic acid, etc.,or with sulfamic acids, such as cyclamic acid etc.

I. Has displayed some interesting pharmacological properties. It is, above all, interesting to note a modifi- (III) 3 4 I /-ca ca ou c rr rm B) H C cu ca oa l L co- -ca cr1 cu c1 I N 0x 011 011 i (I) CO--Il-CH CH CH N I n cn oa N112 In Scheme (A) N-metachlorophenyI-N'-halo-npropylpiperazine is considered as the sum of l-bromo- 3-chloropropane and N-metachlorophenyl-piperazine.

First of all a reaction is carried out between an alkaline salt of 3,4-diethyl-A -l,2,4-triazolin-5-one and l-bromo-3-chloropropane in a suitable solvent, such as, for instance, alcohol. Later on, l-(3-ch1oropropyl)- 3,4-diethyl-A -l ,2,4-triazolin-5-one is heated for a few hours with N-metachlorophenyl-piperazine in an inert solvent in the presence of an HCI acceptor.

In Scheme (B) N-metachlorophenylpiperazinopropyl chain is built on 3,4-diethyl-A -1,2,4- triazolin-S-one in three subsequent operations. The first one, which is common also to Scheme (A), consists in the preparation of l-(3-chloropropyl)-3,4- diethyl-A -l,2,4-triazolin-5-one. The product is then heated with an excess of diethanolamine and l-(3-bishydroxy-ethylaminopropyl)-3,4-diethyl-A -l ,2,4- triazolin-S-one is isolated. The metachlorophenylpiperazine ring is then built on to this compound, first by treating the product with thionyl chlorideand later on with metalchloroaniline, even without isolating the a ion .pr9qy, t

The pharmacological effect of the compound of this invention (1) was evaluated in accordance with the following known procedures:

Effects on behavior (rats and mice) Irwin. S. Pharmacologic Techniques in Drug Evaluation Year Book Medical Publishers, Chicago, 1964. p. 36.

Effects on conditioned reflexes on mice Bovet, D.', Gatti, G.L. and Frank, M. Sci. Reps. Ist.

1 Super. Sanita., 1961, 1, 127.

Effects on spasms provoked by serotonin (50 ug./kg.) and by histamine (l6 ug./kg.) in guinea pigs Konzett, H. and Roessler R. Arch. Exp. Path. Pharmakol., 1940, 195, 71.

The compound of the invention can be administered either alone or in admixture with a pharmaceutical carrier which is selected with regard to the intended route of administrationand standard pharmaceutical practice, as is well known in the art. Compound (I) may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of 'elixirs or suspensions containing flavoring or coloring agents. (I) May be injected parenterally, for

example, intramuscularly or subcutaneously. For parenteral administration, (I) may best be used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic. (I) Can be administered alone or in admixture with other active agents.

With respect to dosage levels, the physician in any event will be easily able to determine the actual dosage which will be the most suitable for any individual patient and it will vary with age, the weight and response of the particular patient. In general the daily dose will range from 50 to 300 mg., according to the cases treated, and an individual dose will contain about 25 mg. of the active compound (I).

ACUTE TOXICITY OF (I) IN MICE AND RATS 3,4-Diethyl-A -l,2.4-triazolin-5-one (62 g.) is dissolved in anhydrous dioxane (about 500 ml.) NaH (21 g.) in a 50 percent oily suspension is added. The solution is heated for 30 minutes under reflux and N- 5 metachlorophenyl-N'-(3-chloro-n-propyl)piperazine (l 19 g.) is added under stirring. The solution is heated for 20 hours under reflux. The solvent is then eliminated under reduced pressure and the residue is treated with 2N HCl. The solution is washed with ether so as to eliminate the oil present in the hydride solution, and made alkaline with 50% K CO It is extracted with ether and dried, the solvent is eliminated and the residue is distilled under reduced pressure. 115 G. ofa substance are obtained. B.P. 230 at 0.5 mm. The salts were prepared by standard procedures. The hydrochloride, which crystallizes from isopropanol, shows m.p. 197-8C. The sulfate melts at l7880C.. the phosphate at 1646C., the maleate at l223C., the ben- 3-bromo-1-chloropropane (6.6 g.) are added to a solution of Na (0.98 g.) in methanol (20 ml.). The solution is refluxed until the pH becomes neutral, poured into water, extracted with ether; the solvent is eliminated and the residual oil is distilled. l-(3-Chloropropyl)-3,4-

diethyl-A -l,2.4-triazolin-5-one boils at 121 at 0.05

EXAMPLE 3 l-(3-Chloropropyl)-3.4-diethyl -A -1.2.4-triazolin- S-one (1 g.), metachlorophenyl-piperazine (0.9 g.) and triethylamine (0.46 g.) in toluene (25 ml.) are refluxed for 12 hours. The solution is treated with 5N NaOH, extraeted with ether and steam-distilled. The residue from the distillation is extracted with ether and the EXAMPLE 4 l-( 3-Chloropropyl )-3,4-diethyl-A -l .2,4-triazolin- 5-one (1.5 g.) and diethanolamine (1.5 g.) are heated at for 15 hours. The solution is treated with CHCl (10 ml.) and shaken with A1 0 (11/111) (05 g). The so lution is filtered and. after elimination olthe solvent. the residual oil is distilled. 1.4 G. 01' 1-( 3- bishydroxyethylaminopropyl)-3,4-diethyl-A -1.2.4- triazolin-S-one are obtained. B.P. 205.-10 at 0.1 mm. l-(3-Bishydroxyethylaminopropyl)-3,4-diethyl-A 1,2,4-triazolin-5-one (1.3 g.) is treated with thionyl chloride (1.3 ml.) for 30 minutes at 75. The excess of thionyl chloride is eliminated in a rotating evaporator and the residue is dissolved in amyl alcohol (30 ml.).

Metachloroaniline (0.57 g.) is added to the solution which is boiled at in a nitrogen stream for 8 hours. The basic portion is extracted and the solution is steamdistilled. The residue from the distillation is extracted with ether and treated with ethereal l-lCl; l-[3-(4- metachlorophenyl-1-piperazinyl)-propyl]-3,4-diethyl- A -I,2, 4-tria qolin -5-one hydrochloride (m.p. l978 from isopropanol), identical to the one obtained according to Example 1. is obtained.

What is claimed is:

1. 1-[3-(4-meta-Chlorophenyl-1-piperazinyl)- propyll-3,4-diethyl-A-l,2,4-triazolin-5-one of the formula:

or the pharmaceutically acceptable acid-addition salts 

1. 1-(3-(4-META-CHLOROPHENYL-1-PIPERAZINYL)-PROPYL)-3,4DIETHYL-$2-1,2,4 -TRIAZOLIN-5-ONE OF THE FORMULA: 